Ibuprofen for Topical Administration

ABSTRACT

Set forth herein is a preparation of ibuprofen (2-(4-isobutylphenyl) propionic acid) in the free acid form that is suitable for topical administration. The topical ibuprofen formulation is prepared by dissolving the free acid form of ibuprofen, or preparing a homogeneous suspension of the free acid form of ibuprofen, in the presence of a pharmaceutically acceptable solvent so as to produce a topical drug formulation compatible with the penetration of 2-(4-isobutylphenyl) propionic acid through the skin tissue. Topical formulations of ibuprofen can be based on a pharmaceutically acceptable solvent such as, e.g., a pyrrolidone solvent or dimethylacetamide.

REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.13/604,040 filed Sep. 5, 2012, which itself is a continuation of U.S.application Ser. No. 12/557,470 filed Sep. 10, 2009, which itself claimsbenefit of U.S. provisional application Ser. No. 61/095,672, filed Sep.10, 2008, the entire disclosures of all of which are hereby incorporatedby reference.

TECHNICAL FIELD

The present invention relates to topical compositions of ibuprofen andmethods for making and using the compositions.

BACKGROUND

Ibuprofen, an anti-inflammatory, analgesic, and anti-pyretic agent, is amember of a group of drugs known as non-steroidal anti-inflammatorydrugs (NSAIDs). Past formulations of ibuprofen have chiefly made use ofthe water-based form (salt form) of ibuprofen. Ibuprofen in its saltform forms the basis of such drug products as Advil® (potassium saltform of ibuprofen). Use of ibuprofen in its free acid form has beenlimited to formulations intended for oral administration, e.g., Motrin®in tablet and oral suspension. IBU® Ibuprofen Tablets USP (KnollLaboratories, Mount Olive, N.J.) is supplied in tablets for oraladministration.

NSAIDs are highly effective in treating pain and inflammation in joints,muscles and soft tissue, and are generally given orally for a systemiceffect. However, some individuals are unable to tolerate oral intake ofibuprofen. For example, ingestion may result in vomiting, thus leadingto ineffective dosing. Others are able to ingest ibuprofen but, as aresult, develop gastric mucosal lesions. These lesions lead to gastricdiscomfort and abdominal pain.

SUMMARY OF THE INVENTION

The adverse side effects commonly associated with ibuprofen can beavoided by directly administering ibuprofen to an afflicted site in theform of a topical formulation. The inventive ibuprofen formulations setforth herein provide an alternate, topical, form of delivery to relievepain and inflammation, e.g., in muscles, joints and soft tissue, whileovercoming many difficulties in formulating a therapeutically effectivetopical pharmacological composition containing ibuprofen, including lowsolubility of the free acid form of the drug in aqueous solvents, aswell as chemical and physical stability and cosmetic appeal.

In a first illustrative embodiment of the ibuprofen composition of theinvention (hereinafter an “ibuprofen composition”), the ibuprofencomposition includes the free acid form of 2-(4-isobutylphenyl)propionic acid, a pharmaceutically acceptable solvent, e.g., apyrrolidone solvent or dimethylacetamide solvent, and at least oneexcipient.

In related embodiments, the 2-(4-isobutylphenyl) propionic acid can havea half-life of at least six months at 25 degrees Celsius. The solventcan be, e.g., a pyrrolidone solvent, e.g., N-methyl-2-pyrrolidone or2-pyrrolidone, or dimethylacetamide. The 2-(4-isobutylphenyl) propionicacid can be either dissolved or suspended, preferably homogeneouslysuspended, in a particle or nanoparticle form. The excipient can includeone or more of water, a water-soluble excipient, or a water-insolubleexcipient. The composition can also include an emulsifier.

The 2-(4-isobutylphenyl) propionic acid can be in a protonated form. Asused here, “protonated form” means that the ibuprofen is insubstantially protonated form, i.e., at least 90% protonated, preferably95% protonated or even 100% protonated. The excipient can also include abuffer having at least one acid ionization constant, pKa, that is chosenso as to maintain the 2-(4-isobutylphenyl) propionic acid in asubstantially protonated form. The buffer can have a pKa of less than 7.

In accordance with a further embodiment of the invention is a method oftreating inflammation. The method includes selecting a patient in needof therapy and applying a topical composition to the skin of thepatient. The composition includes 2-(4-isobutylphenyl) propionic acid, apharmaceutically acceptable solvent, e.g., dimethylacetamide,N-methyl-2-pyrrolidone, or 2-pyrrolidone, and at least one excipient.

In accordance with another embodiment of the invention is a method ofpreparing a pharmaceutical composition by solubilizing ibuprofen in apharmaceutically acceptable solvent, creating an active drug-containingsolution by combining the solubilized ibuprofen with a skin conditionerand a preservative, creating an aqueous solution containing aconditioner, a pH stabilizer and a preservative, creating an emollientphase by combining an emulsifier, a preservative, an oil and astabilizer, combining the emollient phase and the aqueous solution,homogenizing to create a homogenized mixture, and adding the active drugcontaining solution to the homogenized mixture under temperatureconditions avoiding degradation of the ibuprofen.

In related embodiments, the pyrrolidone solvent can be eitherN-methyl-2-pyrrolidone or 2-pyrrolidone. At least one of the steps ofcreating an aqueous mixture, creating an emollient phase, combining andhomogenizing can include adding a first amount of heat. A second amountof heat can then be removed prior to the adding the active drugcontaining solution to create the temperature conditions that avoiddegradation of the ibuprofen.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing features of the invention will be more readily understoodby reference to the following detailed description, taken with referenceto the accompanying drawings, in which:

FIG. 1 is a flow diagram for a process of formulating a topicalibuprofen composition in accordance with an embodiment of the invention;and

FIG. 2 is a flow diagram for formulating a topical ibuprofen compositionin accordance with another embodiment of the invention in which thecomposition includes both aqueous and oily ingredients.

DETAILED DESCRIPTION

Set forth herein is a preparation of ibuprofen in the free acid formthat is suitable for topical administration. The topical ibuprofenformulation is prepared by dissolving the free acid form of ibuprofen insolution, or suspending the free acid form of ibuprofen in the presenceof a pharmaceutically acceptable solvent so as to produce a topical drugformulation compatible with the penetration of the ibuprofen through theskin tissue. Topical formulations of ibuprofen using a pharmaceuticallyacceptable solvent, e.g., a pyrrolidone solvent or dimethylacetamide.

Definitions. The following terms shall have the meanings indicated,unless the context otherwise requires.

Forms of ibuprofen useful in the invention include the acid form, orfree acid form, of ibuprofen, known by the chemical names:(±)-2-(4-isobutylphenyl) propionic acid; 2-(4-iso-butylphenyl) propionicacid; (4-isobutyl-alpha-methylphenylacetic acid; and4-iso-butyl-alpha-methylphenylacetic acid and synonyms thereof known tothose skilled in the art (hereafter collectively referred to as“2-(4-isobutylphenyl) propionic acid”). Forms of ibuprofen suitable forthe invention expressly include racemic mixtures of 2-(4-isobutylphenyl)propionic acid and individual stereoisomers thereof. It is understoodthat “ibuprofen in the acid form” indicates that the ibuprofen moleculesin the composition are predominantly or entirely protonated, asdistinguished from a salt of the conjugate base or a buffered mixture ofacid and base forms.

A “nanoparticle” is a particle having one or more dimensions of 1000nanometers or less.

“Half life” of an active ingredient of a composition means the durationof time elapsing from creation of the formulation until degradation ofthe formulation reduces by 50% the concentration of the activeingredient in the formulation.

“Degradation” of a formulation including an active ingredient includes aprocess operative over time by which increasing amounts of the activeingredient are inactivated by at least one of chemical reaction andphysical separation (such as precipitation).

A “formulation” is a preparation in which various chemical substancesare combined with an active ingredient, e.g., ibuprofen. As used herein,a formulation includes a composition of the invention in the form of anointment, cream, lotion, gel, salve or the like, or a composition byitself, for topical application or delivery of the drug to a patient. Insome embodiments, as appropriate, a formulation can also include adelivery system (such as a patch) impregnated with or containing acomposition including an active ingredient, suitable for topicalapplication. The ibuprofen of the composition can permeate the skin toprovide therapeutically effective transdermal delivery of the ibuprofento a locally affected region.

A “pharmaceutically acceptable solvent” is one or more of the solventslisted as being acceptable by the Federal Food and Drug Administration(FDA) in its Inactive Ingredients Database(www.accessdata.fda.gov/scripts/cder/lig/index.cfm, last visited 10 Sep.2009). A pharmaceutically acceptable solvent must be one whichfacilitates solubility of the free acid form of ibuprofen, or must beone which facilitates formation of a homogeneous suspension of the freeacid form of ibuprofen, to at least 1%, or to at least 5% or 7.5%,preferably to at least 10%, and most preferably to at least 20%, of theformulation on a weight percent basis.

In illustrative embodiments of the invention, ibuprofen compositions arephysically and chemically stable and so resist degradation. In anembodiment, topical application of the compositions are used to treatinflammatory-related disorders of a patient. In specific embodiments,pharmaceutically acceptable solvent, e.g., a pyrrolidone solvent or adimethylacetamide solvent, dissolves the free acid form of ibuprofen. Afurther embodiment of the invention includes a method for manufacturingthe composition.

In an embodiment, ibuprofen is formulated into an ointment composition(e.g. a cream, lotion, gel, salve or like formulation) for topicalapplication. The ibuprofen of the composition can permeate the skin toprovide therapeutically effective transdermal delivery of the ibuprofento a locally affected region (such as an inflamed muscle or joint), toprovide anti-inflammatory and/or pain relief. Optionally, the ibuprofencan permeate to a degree that is sufficient to effect systemic therapy(e.g., to treat a headache or flu). The topical application oftherapeutic doses of ibuprofen can result in faster and more effectiverelief from pain and inflammation than is typically achieved by oralingestion. When applied topically for local relief, total body dosagesshould be much lower than with orally ingested ibuprofen, thus reducingside-effects.

The table below shows ingredients that can be used in compositionsaccording to embodiments of the invention. The ibuprofen can beenantiomerically pure (e.g., the active S enantiomer) or can be racemic.The ibuprofen can be dissolved or in particulate form. Examples ofparticulate ibuprofen include micoparticles or nanoparticles withdiameters ranging from 10⁻⁴ (100 microns) to 10⁻⁹ meters (1 nanometer).Preferably, a particulate acid form of ibuprofen useful for preparing ahomogeneous suspension in a pharmaceutically acceptable solventaccording to the invention is between 1 and 20 microns in diameter, andmore preferably less than 1 micron in diameter.

Particles can be produced by microfluidizing and fluid energy milling(see, e.g., U.S. Pat. Nos. 4,851,421; 4,826,689; 4,540,602; 5,145,684and 6,555,130, each of which is hereby incorporated by reference), acavitation process, or other suitable methods known to those skilled inthe art. Microfluidics-based homogenizers, also referred to as“nano-equipment”, are designed to reduce particle sizes by differentmechanisms, from multiple microns in diameter to submicron or nanometersized diameters. These in turn can assist in maximizing the penetrationof an agent through the skin and/or into the body by other means ofdelivery.

In an embodiment, the ibuprofen is either dissolved or suspended in apharmaceutically acceptable solvent. In an embodiment the solvent ispharmaceutically acceptable solvent, e.g., a pyrrolidone solvent, forexample, a solvent that includes one or more of N-methyl-2-pyrrolidone,and 2-pyrrolidone. Alternately or in addition, the solvent can includedimethylsulfoxide, dimethylformamide, dimethylacetamide, ordimethylisosorbide. The ibuprofen can be dissolved in its free acidform.

The formulation can also include at least one excipient, which is asubstance serving as a vehicle for the ibuprofen. A variety ofexcipients can be used. The excipients can be present at, e.g., between1 to 20% wt % of the solvent system. The excipient can include a skinconditioner, an emulsifier, an emulsion stabilizer, a viscositymodifier, a pH buffer, a preservative, an emollient, or a combinationthereof.

Examples of skin conditioners include L-arginine, menthol, andeucalyptus oil or combinations of these. The skin conditioner can be,for example, 0.1 to 20%, e.g., 0.5% or 1.0%, of the composition byweight. In one preferred embodiment, the formulation can containL-arginine 0.5% as a vasodilator. Nitric oxide (NO) is producedendogenously from arginine in a reaction catalyzed by nitric oxidesynthase. NO is one of the primary agents eliciting a vasodilatoryresponse by relaxing vascular smooth muscle, thereby producing anincrease in skin blood flow and assisting the ibuprofen to the painfularea (e.g., synovial tissue in osteoarthritis).

Examples of emulsifiers include glyceryl stearate, lecithin, andpolyoxyl 40 hydrogenated castor oil. The skin emulsifier can be 1 to 40%of the composition by weight.

Examples of viscosity modifiers include xantham gum, Veegum® (R.T.Vanderbilt Co., Inc., Norwalk, Conn.), and Permulen™ (LubrizolCorporation, Cleveland Ohio). The viscosity modifier can be, forexample, 0.1 to 15% of the composition by weight.

Ibuprofen has a logarithmic acid dissociation constant, or acidionization constant (pKa) of about 4.4. An example of a pH buffer (i.e.,a pH stabilizer) is citric acid, adjusted to an appropriate pK. Citricacid has three ionization constants, with pKa's of 3.15, 4.77, and 6.40respectively. Thus, as is known in the art, by choosing a buffer ofappropriate pH and concentration for a given concentration of ibuprofen,citric acid is capable of buffering ibuprofen in a substantiallyprotonated form, e.g., about 90% protonated to about 100% protonated.The buffer concentration can be, for example, 0.1 to 15% of thecomposition by weight. Alternately, ibuprofen can be used as a free acidwithout the use of a buffer.

A preservative can be used to prevent spoilage due to microbial growthor oxidation. Examples of preservatives include methylparaben andpropylparaben, or combinations of these. The preservative is usuallyincluded at 0.1 to 5% of the composition by weight, as adjudged by oneskilled in the art.

An emollient can be included in the composition to soften and soothe theskin, or to correct dryness or scaling of the skin. Examples of usefulemollients include without limitation lemon oil, olive oil, siliconeoil, mineral oil, petrolatum, vegetable wax and mixtures thereof.Emollients can be included at a concentration of, e.g., 1 to 20% of thecomposition by weight.

In an optional embodiment, the excipient can includes water, so as to beat partially aqueous. Care should be taken however that the waterconcentration is not so high as to cause degradation of the ibuprofenunder relevant storage conditions. Alternatively, the excipient can benon-aqueous.

The composition can be effective in treatment of conditions includingrheumatoid arthritis, osteoarthritis, periarticular disorders and softtissue injuries, postoperative pain, musculoskeletal pain or the pain ordiscomfort associated with gout or morning stiffness.

The composition can be applied to the affected area and massaged in.Alternately, in another “formulation” (as that term is defined above),the ibuprofen composition can be combined with or impregnated into apatch or other device that is applied to the surface of the skin. In anembodiment, a reservoir of solvent (e.g., 2-pyrrolidone orN-methyl-2-pyrrolidone) is slowly released from a patch reservoir,enabling a layer of ibuprofen to be dissolved. In an embodiment, thecomposition can deliver ibuprofen with a time-release orextended-release action (e.g., delivery over 1-8 hours).

In embodiments, because the ibuprofen is substantially protonated andcompatible with the solvent/excipient system, it can have an extendedshelf-life (e.g., a half-life of 6 months or more at 25° C.).

% (by Component Class weight) Examples Active ingredient   1-50Ibuprofen Racemic Enantiomerically pure Particulate NanoparticulateSolvent   1-20 N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide,dimethylformamide dimethylacetamide, dimethylisosorbide Skin conditioner0.1-20 L-arginine, menthol, eucalyptus oil Emulsion stabilizer 0.5-15Vitamin E TPGS Emulsifier   1-40 glyceryl stearate, lecithin, polyoxyl40 hydrogenated castor oil Viscosity modifiers 0.1-15 Xanthum gum,Veegum, Permulen Buffer 0.1-15 Citric acid Preservative 0.1-5Propylparaben, methylparaben Emollient   1-20 Lemon oil, olive oil,silicone oil

The flow diagram of FIG. 1 shows a process for manufacturing anibuprofen composition according to an embodiment of the presentinvention. First, ibuprofen is dissolved in a solvent (step 100). Thesolvent can include N-methyl-2-pyrrolidone, 2-pyrrolidone,dimethylsulfoxide, dimethylformamide. dimethylacetamide,dimethylisosorbide or mixtures thereof in amounts sufficient to dissolvethe ibuprofen. The ibuprofen amount and concentration can be selected toresult in 1-50% ibuprofen in the final formulation. Then, one or moreexcipients are added (step 110). In an embodiment, one or more mixturesof excipients are heated. The excipients can be blended or homogenized.Multiple pools of excipient ingredients can be combined prior to addingthe active ibuprofen ingredient. The excipients can be cooled prior tocombining with the ibuprofen.

The flow diagram of FIG. 2 shows a process for manufacturing anibuprofen composition according to another embodiment of the presentinvention. In a first vessel, ibuprofen is dissolved in a solvent. Thesolvent can include N-methyl-2-pyrrolidone, 2-pyrrolidone,dimethylsulfoxide, dimethylformamide. dimethylacetamide,dimethylisosorbide or mixtures thereof in amounts sufficient todissolved the ibuprofen. Optionally, one or more skin conditionersand/or preservatives are added to the ibuprofen-solvent mixture (step210).

In a second vessel, the water soluble excipient ingredients are combinedto form an aqueous solution (step 220). Toward the goal of obtaininghomogeneity in the formulation, the ingredients can be heated (by addinga first amount of heat) and/or mixed (step 230), either during or afterthe combination. For example, one or more pH buffers, preservatives andskin conditioners can be combined while heating to 70±10° C. The mixingprocess can include stirring, blending or other homogenizationtechniques known in the art.

In a third vessel, hydrophobic (oily) ingredients are combined (step240). To promote homogeneity in the formulation, the ingredients can beheated and/or mixed (step 250), either during or after the combination.The contents of the third vessel can be heated, for example, to 70° C.The mixing process can include stirring, blending or otherhomogenization techniques known in the art. Optionally, emulsifiers orother ampiphilic ingredients can be combined with either the aqueoussolution in the second vessel or the oily ingredients in the thirdvessel.

The contents of the second vessel (aqueous phase) and third vessel (oilphase) can then be combined (step 260) and optionally homogenized. Thecombined mixture can then be cooled (e.g., heat removal to reach 40° C.)and combined with the contents of the first vessel (dissolved ibuprofenand other optional ingredients. Cooling of the mixture (by removing asecond amount of heat) creates conditions that avoid degradation of theibuprofen. For example, cooling prior to adding the ibuprofen can avoiddegradation of the ibuprofen to a substantial degree (e.g., <20%degradation).

Stability Procedure:

Test formulations are stored in high density polyethylene jars (2 and 4ounce) with screw caps. The containers are placed at 40° C., 22° C. and4° C. (degrees Celsius) for periods of time and evaluated for theintegrity of the formulation and emulsion stability as well as forquantitative analysis of the ibuprofen content of the batch. Theformulation and emulsion integrity are evaluated visually for thepresence of phase separation, color, texture or other changes as notedat the time of initial preparation. The quantitative analysis of theibuprofen is performed with a qualified rugged HPLC method.

Ibuprofen formulations prepared according to embodiments describedherein are stable, including hydrolytically stable. For example, morethan 90% of the therapeutic or biochemical activity of the ibuprofen inthe formulation will be active after storage at room temperature (˜20-25degrees Celsius) for at least six months.

Example 1

TABLE 1 Wt % (of excipient) Phase A L-Arginine Base 0.2 Methylparaben0.2 Water 5 Phase B IBU (USP grade) 3.5 Menthol 2 Eucalyptus Oil 2N-methyl-2-pyrrolidone 1 Phenoxyethanol 0.7 Phase C Cetyl Alcohol 5Soybean Oil 17.5 Glyceryl Stearate 6 Beeswax 22 Petrolatum 10 EthylOleate 12.8 Vitamin E TPGS 2 Capric Glyceride 10 Propylparaben 0.1TOTAL: 100

The formulation of Example 1 is prepared as follows. In Tank 1, dissolve(±)-2-(4-isobutylphenyl) propionic acid into N-methyl-2-pyrrolidoneuntil completely solubilized. Add the remaining ingredients of Phase Band mix until completely dissolved. In the Main tank, add theingredients of Phase C, mix while heating to 70° C. In tank 2, add theingredients of Phase A, mix while heating to 70° C. Transfer thecontents in Tank 2 into the main tank, mix for 10 minutes, and cool to40° C. (degrees Celsius) or less. Transfer contents in Tank 1 into MainTank at 40° C. (degrees Celsius) or less. Mix until blended (˜20minutes).

Example 2

TABLE 2 Wt % (of excipient) Phase A L-Arginine Base 0.2 Methylparaben0.2 Water 5 Phase B IBU (USP grade) 20 Menthol 2 Soybean Oil 14.8Eucalyptus oil 2 Phenoxyethanol 0.7 Dimethylacetamide 2 Phase C Beeswax18 Petrolatum 10 Glyceryl Stearate 5 Cetyl Alcohol 5 Vitamin E TPGS 2Capric Glyceride 10 Ethyl Oleate 3 Propylparaben 0.1 TOTAL: 100

The formulation of Example 2 is prepared as follows. In Tank 1, dissolvementhol into eucalyptus oil until completely solubilized; add remainingingredients of Phase B and pass through nano-equipment to reduce theparticle size. In the main tank, add the ingredients of Phase C, mixwhile heating to 70° C. In tank 2, add the ingredients of Phase A, mixwhile heating to 70° C. Transfer the contents from Tank 2 into MainTank, mix for 10 minutes; cool to 40° C. (degrees Celsius) or less.Transfer the contents of Tank 1 into the Main Tank at 40° C. (degreesCelsius) or less. Mix until blended (˜20 minutes).

Example 3

TABLE 3 Preparation of Batch No. 176ZX03 (% w/w) Ibuprofen in free acidform 10 KOH 2 L-Arginine Base 0.5 Carbopol ® 980NF (2.5%) 4 Veegum ® HV(10%) 35 Methylparaben 0.2 Syloid 244 FP 4 Phenoxyethanol 0.7 Water 14Menthol 5 Eucalyptol 5 N,N-dimethylacetamide 3 Olive Oil 5 Lemon Oil 0.5Vitamin E TPGS 2 Propylparaben 0.1 Glyceryl Monostearate 7 DC Elastomer10 2 TOTAL 100

One hundred grams (100 g) of a 2.5% Carbopol® 980NF solution is preparedas follows. While heating 97.5 g water to 70° C., add 2.5 g Carbopol®980NF powder with strong mixing (i.e., such that a vortex should turn).Mixing is continued until the solution is hydrated and free of clumps at70° C. The solution is removed from heat and left at room temperatureovernight, and then mixed again before use.

One hundred grams (100 g) of a 10% Veegum® HV solution is prepared asfollows. While heating 90 g of water to 70° C., 10 g Veegum® HV is addedwith strong mixing (i.e., a vortex should turn). Mixing is continued for30 minutes at 70° C. The mixture is removed from the heat and mixing iscontinued for another hour. The mixture is left at room temperatureovernight, and then mixed again before use.

The formulation of Example 3 is prepared as follows. In Tank 1, thementhol, eucalyptol, and dimethylacetamide (DMA) are mixed togetheruntil the solution is completely dissolved and clear. Syloid 244 FP isthen added to form a homogenous gel. In Tank 2 is placed the olive oil,lemon oil, Vitamin E TPGS, propylparaben, glyceryl monostearate, and DCElastomer 10, and heated to 70° C. (degrees Celsius) while mixing. InTank 3 (the main tank) is added the designated amount of 10% Veegum® HVsolution and water together, and mixed for 15 minutes. The ibuprofen,potassium hydroxide (KOH), methylparaben, and L-Arginine base are thenadded, heated to 70° C. (degrees Celsius) and mixed for about 15 minutesuntil no solid exists. At 70° C. (degrees Celsius), the oil phase fromtank 2 is added to tank 3 and mixed for 5 minutes before starting tocool the tank. While cooling, 2.5% Carbopol® 980NF solution is added.When at 40° C., phenoxyethanol and the homogeneous gel from tank 1 areadded to tank 3, and mixed for another 30 minutes.

After testing for stability, the ibuprofen active ingredient in theBatch 176ZX03 formulation was stable at 22 degrees Celsius (22° C.) formore than 7 months with no degradation in the ibuprofen concentrationand also no deterioration in the integrity of the formulation oremulsion.

Example 4

TABLE 4 Preparation of Ibuprofen Batch No. BC1-170C % (w/w) Ibuprofen7.5 Arginine 0.5 Methylparaben 0.2 Citric Acid 0.2 Xanthan Gum 1 Menthol5 Eucalyptus Oil 5 Phenoxyethanol 0.7 1-Methyl-2-Pyrrolidinone 2 Water51.3 Olive Oil 5 Lemon Oil 0.5 Vitamin E TPGS 2 Glyceryl Stearate 8Stearyl Alcohol 8 ST Elastomer 10 3 Propylparaben 0.1 TOTAL: 100

The formulation of Example 4 is prepared as follows. In Tank 1, mixmenthol, eucalyptus oil, 1-methyl-2-pyrrolidinone, phenoxyethanol, andibuprofen together until the solution is completely dissolved and clear.In Tank 2 put the olive oil, lemon oil, Vitamin E TPGS, propylparaben,glyceryl stearate, DC Elastomer 10 and stearyl alcohol together and heatto 70° C. (degrees Celsius) while mixing. In Tank 3 (Main tank), add themethylparaben, L-arginine base, and citric acid into water. Add xanthangum in with strong mixing, heat to 70° C. (degrees Celsius) and mix for15 minutes until no solid exists. At 70° C. (degrees Celsius), add oilphase from tank 2 into tank 3. Mix for 5 minutes, and start to cool thetank. At 40° C. (degrees Celsius), add solution in tank 1, and mix foranother 30 minutes.

The formulation BC1-170C was found to be stable at 40° C. (degreesCelsius) for 13 months.

The embodiments of the invention described above are intended to bemerely exemplary; numerous variations and modifications will be apparentto those skilled in the art. All such variations and modifications areintended to be within the scope of the present invention as defined inany appended claims.

What is claimed is:
 1. A physically and chemically stable topicalpharmacological composition prepared by a process comprising the stepsof: (a) creating a first mixture by dissolving ibuprofen in a solvent;(b) creating second mixture comprising at least one water solubleingredient; (c) creating a third mixture comprising at least onehydrophobic ingredient; (d) creating a fourth mixture by combining thesecond mixture and the third mixture; and (e) combining the firstmixture and the fourth mixture to create the physically and chemicallystable topical pharmacological composition.
 2. The composition of claim1, wherein step (b) further comprises heating the at least one watersoluble ingredient.
 3. The composition of claim 2, wherein the at leastone water soluble ingredient is heated to about 70° C.
 4. Thecomposition of claim 1, wherein step (c) further comprises heating theat least one hydrophobic ingredient.
 5. The composition of claim 4,wherein the at least one hydrophobic ingredient is heated to about 70°C.
 6. The composition of claim 1, wherein step (d) further comprisescooling the fourth mixture.
 7. The composition of claim 6, wherein thefourth mixture is cooled to about 40° C.
 8. The composition of claim 1,wherein the solvent is a pyrrolidone solvent.
 9. The composition ofclaim 8, wherein the solvent is selected from the group consisting ofN-methyl-2-pyrrolidone and 2-pyrrolidone.
 10. The composition of claim1, wherein the solvent is water.
 11. The composition of claim 1, whereinthe solvent is dimethylacetamide.
 12. The composition of claim 1,wherein the solvent is selected from the group consisting ofdimethylsulfoxide, dimethylformamide, and dimethylisosorbide.
 13. Amethod for treating inflammation in a patient in need of therapy,comprising applying to the skin of the patient the stable topicalpharmacological composition of claim 1.